Tobacco Smoking, Genes &Nicotinic Receptors Habitual tobacco smoking is a complex trait with strong genetic influences. Genetic factors are estimated to account for 50-72% of the risk for developing nicotine dependence. The nicotinic acetylcholine receptor (nAChR) is the initial site of action of nicotine, the addictive chemical constituent of tobacco smoke and thus, is a primary candidate to carry genetic effects for tobacco smoking between generations. nAChR containing the 22-subunit (22-nAChR) in combination with 14 subunits are the most prevalent nAChR in brain, and are linked to the addictive properties of tobacco smoking. In our previous proposal, for aim 1, we demonstrated using [123I]5-IA 85380 SPECT imaging that these receptors are higher (26-36%) in the striatum, and throughout the cerebral cortex and cerebellum in tobacco smokers versus nonsmokers. For aim 2 we evaluated the normalization of the receptor over the first month of abstinence, and in addition, evaluated in smokers that were able to abstain from smoking for longer periods of time up to 12 weeks of abstinence. The findings from this aim were very heterogenous, with some subjects showing decreases ranging from 4% to 43% in nAChR availability over the first month of abstinence and others showing no change. We have hypothesized that the variability in the regulatory effects of habitual tobacco smoking on nicotinic receptor availability is genetically determined. In the present proposal, we seek to validate this hypothesis through the following specific aims: 1) to determine if 22-nAChR availability is genetically determined in European-American never smokers. 2) to determine if the adaptive increase in 22-nAChR availability in European-American smokers is genetically determined and 3) to determine if the change in 22-nAChR availability over the first month of abstinence in smokers is genetically determined. The findings from these studies may provide definitive genetic and neurochemical phenotypic evidence that will allow in future studies for smokers to be stratified and tested for responses to various smoking cessation treatments. PUBLIC HEALTH RELEVANCE: Smoking is the leading known cause of preventable death and disease. Despite the debilitating medical, economic and social costs of cigarette smoking, people continue to smoke. The persistence of this destructive behavior is a consequence of insufficient smoking cessation treatments to assist smokers in their efforts to quit smoking. The nicotinic acetylcholine receptor (nAChR) is a likely neurochemical substrate of the addiction to cigarette smoking. These studies will define the genes and brain chemicals that may help to design treatment studies that will ultimately help tailor smoking cessation treatments, they will decrease the incidence of smoking-related deaths and disease that plague the world today.